Abstract PR009: Investigating dynamics of the mitochondrial network in triple negative breast cancer chemotherapy resistance
Authors: Lily Baek, Mariah Berner, Junegoo Lee, Katherine Pendleton, Karen Wang, Emily B. Goff, James P. Barrish, Bora Lim, Michael T. Lewis, Philip L. Lorenzi, Weston Porter, Gloria V. Echeverria
Journal: Cancer Research (2022)

Abstract Triple negative breast cancer (TNBC) is an aggressive disease with extremely limited targeted therapeutic options. Thus, standard cytotoxic chemotherapies (typically sequential and/or combined anthracyclines, taxanes, and/or platinums) remain a mainstay treatment for this subtype of breast cancer. Nearly 50% of TNBC patients harbor substantial residual cancer burden following standard chemotherapy treatment, leading to high rates of recurrence and death (PMID:28135148). Using longitudinal biopsies from orthotopic patient-derived xenograft (PDX) models and TNBC patients, we found that residual tumors following chemotherapy transitioned to a unique metabolic state characterized by high mitochondrial oxidative phosphorylation (oxphos). This metabolic state was transient, with tumors reverting to their baseline glycolysis-high phenotype when they were allowed to regrow in the absence of treatment. Using genomic sequencing and cellular barcode-mediated clonal tracking, we found this mechanism of chemoresistance arose in the absence of clonal selection, suggesting chemotherapy induced plastic (i.e., non-genomic) programs enabling cell survival following treatment. Oxphos inhibition using a specific inhibitor of electron transport chain Complex I (IACS010759; PMID:29892070) was significantly more efficacious against residual, rather than treatment-naive tumors (PMID:30996079), providing evidence that dynamic metabolic phenotypes represent targetable therapeutic vulnerabilities for TNBC. Mechanisms controlling mitochondrial bioenergetics are numerous but their roles in driving metabolic phenotypes of chemoresistant TNBC are not understood. We find that residual tumor cells following chemotherapy treatment have altered mitochondrial network morphology. Mitochondrial fission and fusion are well established regulators of mitochondrial morphology, yet their functional impacts on bioenergetic output of mitochondria is highly context dependent. Our analyses of mitochondrial structure in TNBC cells and PDX tumors reveal that while DNA-damaging chemotherapeutics (anthracyclines, platinums) increased mitochondrial elongation, microtubule-stabilizing chemotherapeutics (taxanes) increased mitochondrial fragmentation. This was accompanied by increased or decreased oxphos rates and mitochondrial content, respectively. Interestingly, these structural changes were reverted in PDX tumors that were allowed to regrow in the absence of treatment, suggesting mitochondrial adaptations are plastic in vivo. Using pharmacologic agents in TNBC cells, we found that mitochondrial fusion increased oxphos and chemoresistance, whereas mitochondrial fission decreased oxphos and chemoresistance. Further, knockdown of OPA1 or MFN2, mediators of mitochondrial inner and outer membrane fusion, respectively, diminished mitochondrial fusion, oxphos, and chemoresistance. Based on these findings, we hypothesize therapeutic targeting of mediators of mitochondrial network adaptability may be a promising strategy to overcome plastic metabolic states indued by chemotherapeutics in TNBC. Citation Format: Lily Baek, Mariah Berner, Junegoo Lee, Katherine Pendleton, Karen Wang, Emily B. Goff, James P. Barrish, Bora Lim, Michael T. Lewis, Philip L. Lorenzi, Weston Porter, Gloria V. Echeverria. Investigating dynamics of the mitochondrial network in triple negative breast cancer chemotherapy resistance [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr PR009.